I. Technical Field
The present invention relates generally to the fields of microbiology and bacterial genetics. More particularly, it tautomycetin (TTN) analogs and uses therefor.
II. Related Art
The Src homology-2 domain containing protein tyrosine phosphatase-2 (SHP2) is a positive transducer of growth factor- and cytokine-mediated signaling pathways essential for cell proliferation, differentiation, migration, and apoptosis (Neel et al., 2003). The catalytic activity of SHP2 is required for full activation of the Ras-ERK1/2 cascade that is mediated through SHP2-catalyzed dephosphorylation of substrates that are negatively regulated by tyrosine phosphorylation (Neel et al., 2003; Tiganis and Bennett, 2007). Not surprisingly, SHP2 has been identified as a bona fide oncogene from the protein tyrosine phosphatase (PTP) superfamily; gain-of-function SHP2 mutations leading to increased PTP activity are known to cause the autosomal dominant disorder Noonan syndrome as well as multiple forms of leukemia and solid tumors (Tartaglia and Gelb, 2005; Chan et al., 2008). Accordingly, SHP2 represents an exciting target for multiple cancers. Unfortunately, obtaining SHP2 inhibitors with optimal potency and pharmacological properties has been difficult, due primarily to the highly conserved and positively charged nature of the active site pocket shared by all PTP family members.
Tautomycin (TTM) and tautomycetin (TTN) are polyketide natural products originally isolated as antifungal antibiotics from Streptomyces spiroverticillatus and Streptomyces griseochromogens, respectively (Cheng et al., 1987; Cheng et al., 1989) (FIGS. 1A-B). They are structurally similar, differing only in the presence of a spiroketal group on TTM, which is replaced by a dienone moiety in TTN. TTM and TTN were later found to display inhibitory activity against serine/threonine protein phosphatase 1 (PP1) and 2A (PP2A) (MacKintosh and Klumpp, 1990; Mitsuhashi et al., 2001). Despite their similarities in structure and PP1/2A inhibitory activity, TTN, but not TTM, has been identified as a potent immunosuppressor of activated T cells in organ transplantation (Shim et al., 2002; Han et al., 2003). TTN exerts its immunosuppressive activity by blocking T-cell receptor (TCR) induced tyrosine phosphorylation, leading to inhibition of T cell proliferation and cell-specific apoptosis (Shim et al., 2002). Furthermore, TTN has also been suggested as a potential lead for anticancer drug discovery due to its growth inhibitory activity against colorectal cancer cells (Lee et al., 2006). Thus, TTN may serve as a promising lead for the development of new immunosuppressive and anti-tumor agents. To this end, identification of the cellular target(s) of TTN will significantly advance the progress toward TTN-based therapeutics. Strikingly, although TTM and TTN exhibit similar potency toward PP1/PP2A, TTM, unlike TTN, has no effect on tyrosine phosphorylation in T cells and does not elicit any immunosuppressive activity (Shim et al., 2002). Consequently, the immunosuppressive activity of TTN is unlikely related to its PP1/PP2A inhibitory activity and instead may be mediated by an effect on a PTP.